Transdermal delivery, i.e. the ability to deliver pharmaceuticals agents into and through skin surfaces, provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and non invasive alternative to traditional administration systems that can provide a straightforward dosage regimen, relatively slow release of the drug into a patient's system, and control over blood concentrations of the drug. In contrast to oral administration, transdermal delivery typically does not produce the plasmatic peaks and valleys created by oral delivery and G.I. tract absorption. Second, transdermal delivery causes no gastrointestinal irritation, does not present restrictions around the time that the drug should be administered or whether or not the patient may eat afterwards. In particular, once-a-day transdermal delivery offers ease of use and is convenient, without the requirement to remember to take a drug at a specific time. Third, transdermal delivery improves patient compliance for patients who cannot swallow medication, for drugs with unpleasant taste and/or undergoing significant metabolism in the liver; the resulting increased bio-availability, which means that smaller doses may be used for the same drug, is responsible for minimized side effects. In contrast to parenteral administration, transdermal delivery typically does not cause pain and/or anxiety associated with needles, and does not present the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the risk of disposal of used needles.
The advantage of transdermal delivery is particularly enhanced in case of hydrophilic drugs, because of the molecular nature of the G.I. tract. As a lipid membrane, the G.I. tract possesses hydrophobic properties, thus the more hydrophilic a drug is, and the more likely it is to be absorbed poorly through the G.I. tract. A well known example of this problem is sodium alendronate, a bisphosphonate, which needs to be administered in very large doses because only a very small fraction of the drug (about 0.6) % is absorbed indeed when administered orally (please refer to FOSAMAX® Tablets and Oral Solutions Prescribing Information, issued by Merck & Co., Inc., the entire content is incorporated herein for information).
However, despite its clear advantages, transdermal delivery also poses inherent challenges, in part because of the nature of skin. Skin is essentially a thick membrane that protects the body by acting as a barrier. Consequently, passive delivery through intact skin necessarily entails the transport of molecules through a number of structurally different tissues, including the stratum corneum, the viable epidermis, the papillary dermis and the capillary walls in order for the drug to gain entry into the blood or lymph system. Each tissue features a different resistance to penetration, but the stratum corneum is the strongest barrier to the absorption of transdermal and topical drugs. The tightly packed cells of the stratum corneum are filled with keratin. The keratinization and density of the cells may be responsible for skin's impermeability to certain drugs. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue.
In recent years, advances in transdermal delivery include the formulation of skin penetration enhancing agents, also known as permeation enhancers. Permeation enhancers are often lipophilic chemicals that readily move into the stratum corneum and enhance the movement of drugs through the skin. Energy-assisted skin permeation techniques also have emerged to improve transdermal delivery, including heat, ultrasound, iontophoresis, and electroporation. But even with these methodologies, only a limited number of drugs can be administered transdermally without problems such as sensitization or irritation occurring.
Transdermal delivery is different from topical delivery. Drugs administered transdermally are absorbed through skin or mucous membranes and provide effects beyond the application site. In contrast, purpose of a topical drug, e.g., antibiotic ointment, anti-acne cream, hair-growing lotion, anti-itching spray, is to administer medication at the site of intended action. Topical medications typically should be designed not to permit significant drug passage into the patient's blood and/or tissues. Topical formulations are often used to treat infections or inflammations. They also are used as cleansing agents, astringents, absorbents, keratolytics, and emollients. The vehicle of a topical treatment, i.e. the non-active component(s) that carries the active ingredient(s), may interact with the active ingredient(s), changing the drug's effectiveness. The vehicle may also cause skin irritation or allergic reactions in some patients. Thus, the vehicle must be selected with extreme care. Topical formulations may be prepared as pastes, gels, creams, ointments, lotions, solutions, or aerosols. Occlusion with household plastic wrap, bandages, plasters, or plastic tape, is often used in conjunction with topical treatments to improve the drug's absorption and its effectiveness. Typically non-occlusive dosage forms are applied to the skin or mucosa and are left uncovered and open in the atmosphere. Because the non-occlusive dosage form is left uncovered, unwanted transfer of the pharmaceutical formulation to the clothing of the user or even to other individuals in close proximity to the user is unavoidable. Other drawbacks of the non-occlusive dosage form include evaporation of the formulation, removal of the formulation from the skin or mucosa, for example, by bathing or by other activities, and the non absorption of the formulation through the skin, which is discussed below.
The inefficiencies of drug permeation across or through the skin or mucosa barriers are known. It is also known that the permeation of a drug in a non-occlusive transdermal or transmucosal dosage form can be as little as 1% and usually is no more than 15%. Thus, a vast majority of the active drug remains unabsorbed on the skin or mucosa surface. Because the vast majority of the drug remains on the skin and does not penetrate the skin or mucosa surfaces, the bioavailability of the particular drug is not optimal, and also a high risk of contamination of other individuals in close proximity to the user is presented by the unwanted transfer of the pharmaceutical formulation in the non-occlusive dosage form.
Problems associated with the unwanted transfer of a particular pharmaceutical formulation to others are well documented. For example, Delanoe et al. reported the androgenization of female partners of volunteers applying a testosterone gel preparation during contraceptive studies (Delanoe, D., Fougeyrollas, B., Meyer, L. & Thonneau, P. (1984): “Androgenisation of female partners of men on medroxyprogesterone acetate/percutaneous testosterone contraception”, Lancet 1, 276-277). Similarly, Yu et al. reported virilization of a two-year-old boy after incidental and unintentional dermal exposure to a testosterone cream applied to his father's arm and back (Yu, Y. M., Punyasavatsu, N., Elder, D. & D'Ercole, A. J. (1999): “Sexual development in a two-year old boy induced by topical exposure to testosterone”, Pediatrics, 104, 23).
Moreover, the patient information brochure for ANDROGEL® (1% testosterone gel from Unimed Pharmaceuticals Inc.) emphasizes the potential for transfer of testosterone to other people and/or clothing and the brochure includes safety measures to be taken by the individual using the non-occlusive dosage form.
One way to overcome or minimize this contamination issue is to physically protect the transdermal dosage form by covering skin with the applied pharmaceutical formulation means of a patch device, a fixed reservoir, an application chamber, a tape, a bandage, a sticking plaster, or the like, which remain on the skin at the site of application of the formulation for a prolonged length of time. This is usually accomplished with occlusive dosage forms.
Occlusive dosage forms present some advantages over non-occlusive dosage forms such as assisting the rate of penetration of drugs across the skin by maintaining the thermodynamic activity of the drug close to its maximum (the thermodynamic activity of a drug in a dermal formulation is proportional to the concentration of the drug and the selection of the vehicle, and according to the laws of thermodynamics, the maximum activity of a drug is related to that of the pure drug crystal). However occlusive dosage forms also exhibit several major drawbacks. For example, occlusive dosage forms present a high potential of local skin irritation caused by the prolonged contact on the skin of the drug, volatiles, vehicle excipients, and the adhesive used to attach the occlusive device, e.g., the patch, to the skin. In addition, the occlusive nature of certain occlusive dosage forms, such as the patch device, also restrict the natural ability of the skin to “breathe,” and thereby increases the risk of irritation.
In addition to the aforementioned drawbacks of occlusive dosage forms, significant serious hazards have been documented regarding the high drug loading that is specific to patches. For example, several cases of abuses with remaining fentanyl in fentanyl patches have been reported. See, Marquardt K. A., Tharratt R. S., “Inhalation abuse of fentanyl patch”, J Toxicol Clin. Toxicol. 1994; 32(1):75-8; Marquardt K. A., Tharratt R. S., Musallam N. A., “Fentanyl remaining in a transdermal system following three days of continuous use.”, Ann Pharmacother. 1995 October; 29(10):969-71; Flannagan L M, Butts J D, Anderson W H., “Fentanyl patches left on dead bodies—potential source of drug for abusers.”, J Forensic Sci. 1996 March; 41(2):320-1. Severe incidental intoxication cases have also been documented. See Hardwick Jr., W, King, W., Palmisano, P., “Respiratory Depression in a Child Unintentionally Exposed to Transdermal Fentanyl Patch”, Southern Medical Journal, September 1997.
Patch products typically contain patient information, which clearly indicate the risks discussed above. For instance, OXYTROL™ (an oxybutynin patch commercialized by WATSON Pharmaceuticals, Inc. USA) contains patient information that indicates the following warning: “Since the patch will still contain some oxybutynin, throw it away so that it can not be accidentally worn or swallowed by another person, especially a child.” The high level of active drug residues is thus a critical drawback of patches. Such accidents could not occur with the use of gel formulations.
Although attempts have been made to overcome drawbacks associated with both occlusive and non-occlusive drug forms, such attempts have been futile. For example, as noted above, one drawback of non-occlusive dosage forms is evaporation of the formulation, which is left open in the atmosphere. The formulation of non-occlusive supersaturated systems could have achieved an ideal merge but transdermal formulations, which rely on supersaturation technologies, present a major drawback of formulation instability, both prior to and during application to the skin due to solvent evaporation. See Davis A F and Hadgraft J—Supersaturated solutions as topical drug delivery systems, Pharmaceutical Skin Penetration Enhancement, Marcel Dekker Inc, New York (1993) 243-267 ISBN 0 8247 9017 0, which is incorporated herein by reference.
Notably, extraordinary physicochemical changes occur with the evaporation of the solvent system, which result in modifications of the concentration of the active agent, which may even lead to drug precipitation, thereby altering the diffusional driving force of the formulation. See Ma et al, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995). Consequently, the percutaneous absorption of the active agent may be quite different from that when the solvent was present.
In addition, controlling drug crystallization is of particular interest for non-occlusive transdermal systems. Campbell et al. resorted to a method of heating a crystalline hydrate to a temperature above the melting point in order to prevent the crystallization of the formulation. See, U.S. Pat. No. 4,832,953. Ma et al found that PVP added to the matrix acts as an effective crystallization inhibitor for norethindrone acetate transdermal delivery systems. See, Int. J. of Pharm. 142 (1996) pp. 115-119). DE-A-4210711 affirms that cholesterol and SiO2 are crystallization inhibitors for 17-.beta.-estradiol transdermal delivery system. WO 95/18603 describes soluble PVP as crystal inhibitor for patch devices and affirms that soluble PVP increases the solubility of a drug without negatively affecting the adhesion or the rate of drug delivery from the pressure-sensitive adhesive composition.
Additionally, the inhibition of crystallization in transdermal devices was reported by Biali et al. See, U.S. Pat. No. 6,465,005 in which it is described that the use of a steroid (estradiol for instance) as an additive in a process of manufacture or storage of a transdermal device acts as a crystallization inhibitor during storage of the device.
Further, transdermal delivery from semi-solid formulations faces opposite requirements. The drug delivery system should enable absorption of an extensive amount of active drug through the skin within the shortest period of time in order to prevent contamination of individuals, transfer to clothing or accidental removing. The drug delivery system should also provide sustained release of the active drug over 24 hours ideally, so that only once-daily application is required. This drug delivery system should also prevent drug crystallization at the application surface area.
Drug delivery systems having such properties may be achieved by combining various solvents. A volatile solvent may be defined as a solvent that changes readily from solid or liquid to a vapor, that evaporates readily at normal temperatures and pressures. Here below is presented data for some usual solvents, where volatility is reflected by the molar enthalpy of vaporization ΔvapH, defined as the enthalpy change in the conversion of one mole of liquid to gas at constant temperature. Values are given, when available, both at the normal boiling point tb, referred to a pressure of 101.325 kPa (760 mmHg), and at 25° C. (From “Handbook of Chemistry and Physics, David R. Lide, 79th edition (1998-1999)—Enthalpy of vaporization (6-100 to 6-115). Stanislaus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, 2001) defined as volatile solvent a solvent whose vapor pressure is above 35 mm Mg when the skin temperature is 32° C., and as non-volatile solvent a solvent whose vapor pressure is below 10 mm Mg at 32° C. skin temperature. Examples of non-volatile solvents include, but are not limited to, propylene glycol, glycerin, liquid polyethylene glycols, or polyoxyalkylene glycols. Examples of volatile solvents include, but are not limited to, ethanol, propanol, or isopropanol.
TABLE 1Enthalpy of vaporization of certain solventstbΔvapH (tb)ΔvapH (25° C.)Ethanol78.338.642.3Propan-2-ol (isopropanol)82.339.945.4Propanol97.241.447.5Butan-2-ol99.540.849.7Butan-1-ol117.743.352.4Ethylene glycol mono methyl ether124.137.545.2Ethylene glycol mono ethyl ether135.039.248.2Ethylene glycol mono propyl ether149.841.452.11,2-Propylene glycol187.652.4Not availableDiethylene glycol mono methyl ether193.046.6Not availableDiethylene glycol mono ethyl ether196.047.5Not available1,3-Propylene glycol214.457.9Not availableGlycerin290.061.0Not available
Numerous authors have investigated evaporation and transdermal penetration from solvent systems. For Example, Spencer et al. (Thomas S. Spencer, “Effect of volatile penetrants on in vitro skin permeability”, AAPS workshop held in Washington D.C. on Oct. 31-Nov. 1, 1986) established that the relationship between volatility and penetration is not absolute and depends on many parameters such as for instance hydration of the tissue or the solubility of the penetrant in the tissue. Stinchcomb et al. reported that the initial uptake of a chemical (hydrocortisone, flurbiprofen) from a volatile solvent system (acetone) is more rapid than that from a non-volatile solvent system (aqueous solution). With an aqueous solution, close to the saturation solubility of the chemical, the driving force for uptake remains more or less constant throughout the exposure period. Conversely, for a volatile vehicle which begins evaporating from the moment of application, the surface concentration of the chemical increases with time up to the point at which the solvent has disappeared; one is now left with a solid film of the chemical from which continued uptake into the stratum corneum may be very slow and dissolution-limited.
Risk assessment following dermal exposure to volatile vehicles should pay particular attention, therefore, to the duration of contact between the evaporating solvent and the skin (Audra L. Stinchcomb, Fabrice Pirot, Gilles D. Touraille, Annette L. Bunge, and Richard H. Guy, “Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents”, Pharmaceutical Research, Vol. 16, No 8, 1999). Kondo et al. studied bioavailability of percutaneous nifedipine in rats from binary (acetone and propylene glycol PG or isopropyl myristate IPM) or ternary (acetone-PG-IPM) solvent systems, compared with the results from simple PG or IPM solvent systems saturated with the drug. (Kondo et al. S, Yamanaka C, Sugimoto I., “Enhancement of transdermal delivery by superfluous thermodynamic potential. III. Percutaneous absorption of nifedipine in rats”, J Pharmaco Biodyn. 1987 December; 10(12):743-9).
U.S. Pat. No. 6,299,900 to Reed et al. discloses a non-occlusive, percutaneous, or transdermal drug delivery system—having active agent, safe and approved sunscreen as penetration enhancer, and optional volatile liquid. The invention describes a transdermal drug delivery system, which comprises at least one physiologically active agent or prodrug thereof and at least one penetration enhancer of low toxicity being a safe skin-tolerant ester sunscreen. The composition comprises an effective amount of at least one physiologically active agent, at least one non-volatile dermal penetration enhancer; and at least one volatile liquid.
U.S. Pat. No. 5,891,462 to Carrara discloses a pharmaceutical formulation in the form of a gel suitable for the transdermal administration of an active agent of the class of estrogens or of progestin class or of a mixture thereof, comprising lauryl alcohol, diethylene glycol mono ethyl ether and propylene glycol as permeation enhancers.
Mura et al. describe the combination of diethylene glycol mono ethyl ether and propylene glycol as a transdermal permeation enhancer composition for clonazepam (Mura P., Faucci M. T., Bramanti G., Corti P., “Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations”, Eur. J. Pharm. Sci., 2000 February; 9(4): 365-72)
Williams et al. reports the effects of diethylene glycol mono ethyl ether (TRANSCUTOL™) in binary co-solvent systems with water on the permeation of a model lipophilic drug across human epidermal and silastic membranes (A. C. Williams, N. A. Megrab and B. W. Barry, “Permeation of oestradiol through human epidermal and silastic membranes from saturated TRANSCUTOL®/water systems”, in Prediction of Percutaneous Penetration, Vol. 4B, 1996). Many references may also illustrate the effect of TRANSCUTOL™ as an intracutaneous drug depot builder well known to one skilled in the art.
U.S. Pat. No. 5,658,587 to Santus et al. discloses transdermal therapeutic systems for the delivery of alpha adrenoceptor blocking agents using a solvent enhancer system comprising diethylene glycol mono ethyl ether and propylene glycol.
U.S. Pat. No. 5,662,890 to Punto et al. discloses alcohol-free cosmetic compositions for artificially tanning the skin containing a combination of diethylene glycol monoethyl ether and dimethyl isosorbide as permeation enhancer.
U.S. Pat. No. 5,932,243 to Fricker et al. discloses a pharmaceutical emulsion or microemulsion preconcentrate for oral administration of macrolide containing a hydrophilic carrier medium consisting of diethylene glycol mono ethyl ether, glycofurol, 1,2-propylene glycol, or mixtures thereof.
U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et al. disclose pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents containing diethylene glycol mono ethyl ether and propylene glycol as solubilizers of ionizable hydrophobic therapeutic agents.
U.S. Pat. No. 6,426,078 to Bauer et al. discloses an oil-in water microemulsion containing diethylene glycol mono ethyl ether or propylene glycol as co-emulsifier of lipophilic vitamins.
Many research experiments have been carried out on diethylene glycol mono ethyl ether (marketed under the trademark TRANSCUTOL™ by Gattefosse) as an intracutaneous drug depot builder. For example, Ritschel, W. A., Panchagnula, R., Stemmer, K., Ashraf, M., “Development of an intracutaneous depot for drugs. Binding, drug accumulation and retention studies, and mechanism depot for drugs”, Skin Pharmacol, 1991; 4: 235-245; Panchagnula, R. and Ritschel, W. A., “Development and evaluation of an intracutaneous depot formulation of corticosteroids using TRANSCUTOL® as a cosolvent, in vitro, ex vivo and in-vivo rat studies”, J. Pharm. Pharmacology. 1991; 43: 609-614; Yazdanian, M. and Chen, E., “The effect of diethylene glycol mono ethyl ether as a vehicle for topical delivery of ivermectin”, Veternary Research Com. 1995; 19: 309-319; Pavliv, L., Freebern, K., Wilke, T., Chiang, C-C., Shetty, B., Tyle, P., “Topical formulation development of a novel thymidylate synthase inhibitor for the treatment of psoriasis”, Int. J. Pharm., 1994; 105: 227-233; Ritschel, W. A., Hussain, A. S., “In vitro skin permeation of griseofulvin in rat and human skin from an ointment dosage form”, Arzneimeittelforsch/Drug Res. 1988; 38: 1630-1632; Touitou, E., Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and Fabin, B., “Enhanced permeation of theophylline through the skin and its effect on fibroblast proliferation”, Int. J. Pharm., 1991; 70: 159-166; Watkinson, A. C., Hadgraft, J. and Bye, A., “Enhanced permeation of prostaglandin E2 through human skin in vitro”, Int. j. Pharm., 1991; 74: 229-236; Rojas, J., Falson, F., Courraze, G., Francis, A., and Puisieux, F., “Optimization of binary and ternary solvent systems in the percutaneous absorption of morphine base”, STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A., Barkhaus, J K., “Use of absorption promoters to increase systemic absorption of coumarin from transdermal drug delivery systems”, Arzneimeittelforsch/Drug Res. 1988; 38: 1774-1777.
Thus there remains a need to provide a pharmaceutically acceptable transdermal or transmucosal pharmaceutical formulation or drug delivery system that exhibits the advantages of both occlusive systems (high thermodynamic activity) and non-occlusive systems (low irritation and sensitization potential, and excellent skin tolerance) while overcoming the disadvantages of these systems. The novel transdermal or transmucosal pharmaceutical formulation of the present invention satisfies this need.
The present invention is directed to the transdermal administration of a nicotine compound and pharmaceutically acceptable salts thereof. The preferred nicotine compound is nicotine, a well know, highly characterized alkaloid that can be isolated from the dried leaves of Nicotiana tabacum. A variety of patents have disclosed nicotine-containing compositions, such as chewing gums, nicotine-impregnated dermal patches, nicotine inhalers and the like: see, e.g., U.S. Pat. Nos., 7,029,692, 6,995,265, 6,828,336, 6,676,959, 6,596,740, 6,479,076, the entire content of which are incorporated herein as reference. Nicotine, the primary alkaloid in tobacco products binds stereo-selectively to nicotinic-cholinergic receptors on autonomic ganglia, the adrenal medulla, neuromuscular junctions and in the brain. Nicotine exerts two effects, a stimulant effect exerted at the locus ceruleus and a reward effect in the limbic system. Intravenous administration of nicotine causes release of acetylcholine, norepinephrine, dopamine, serotonine, vasopressin, beta-endorphin and ACTH. Nicotine is a highly addictive substance. Nicotine also induces peripheral vasoconstriction, tachycardia and elevated blood pressure. Nicotine inhalers and patches are used to treat smoking withdrawal syndrome. Nicotine is classified as a stimulant of autonomic ganglia. Nicotine, or 1-methyl-2-(3-pyridyl)pyrrolidone, is an oily colourless or pale yellow liquid with a pyridine odour, a molecular weight of about 162, an octanol:water partition coefficient (log P) of about 1.2, a dissociation constant (pKa) of about 3.1, a solubility in water of about and a melting point of approximately −79° C. Nicotine is miscible with water below 60° C. (See monograph of nicotin in Clarke's Analysis of Drugs and Poisons, ©Pharmaceutical Press 2005, the entire content of which is herein incorporated as reference). Nicotine is readily absorbed from the gastro-intestinal tract, the buccal mucosa, the respiratory tract, and intact skin, and widely distributed throughout the tissues. Nicotine undergoes extensive first-pass metabolism when administered orally, thus reducing the bioavailability. Oral bioavailability of nicotine is about 30%.
Nicotine numerous commercial uses include utilities such as a fumigant, an insecticide and the like. It is therapeutically valuable in the treatment of the smoking withdrawal syndrome. Nicotine has also been found therapeutically valuable in the treatment of other conditions involving release of dopamine such as attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, schizophrenia, Alzheimer's disease, Parkinson's disease, anxiety and depression (see, e.g., U.S. Pat. Nos. 6,911,475; 6,479,076; 6,034,079, 5,278,176); in the therapeutic angiogenesis and vasculogenesis (see, e.g., U.S. Pat. No. 6,417,205); in the treatment of inflammatory bowel disease (see, e.g., U.S. Pat. No. 6,166,044).
Several drug products containing nicotine are currently marketed (as of July 2006) in the US: see U.S. Food and Drug Administration, Center for Drug Evaluation and Research website, from where the excerpt table herein after is extracted:
DRUG NAMEACTIVE INGREDIENTDOSAGE FORMCOMPANYCOMMITNICOTINETROCHE/LOZENGE;GLAXOSMITHKLINEPOLACRILEXORALCONSHABITROLNICOTINEFILM, EXTENDEDNOVARTISRELEASE;TRANSDERMALNICODERM CQNICOTINEFILM, EXTENDEDSANOFI AVENTIS USRELEASE;TRANSDERMALNICORETTENICOTINEGUM, CHEWING;GLAXOSMITHKLINEPOLACRILEXBUCCALNICORETTENICOTINEGUM, CHEWING;GLAXOSMITHKLINE(MINT)POLACRILEXBUCCALNICOTINENICOTINEFILM, EXTENDEDSANORELEASE;TRANSDERMALNICOTINENICOTINEGUM, CHEWING;PERRIGOPOLACRILEXPOLACRILEXBUCCALNICOTROLNICOTINESPRAY, METERED;PHARMACIA ANDNASALUPJOHNFILM, EXTENDEDRELEASE;TRANSDERMALINHALANT; ORALPROSTEPNICOTINEFILM, EXTENDEDAVEVARELEASE;TRANSDERMAL
However, the herein above drug products, and more particularly transdermal patches, are not free of drawbacks.
Inherently to the occlusive nature of the transdermal patches, nicotine transdermal systems are often reported to cause skin irritation. See, for instance, Greenland et al. in “A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch”, Drug Saf. 1998 April; 18(4):297-308: the meta-analysis represented a synthesis of data from 41 groups of nicotine patch recipients totaling 5501 patients, and 33 groups of placebo recipients totaling 3752 patients. The incidences of several minor adverse effects were clearly elevated among the nicotine-patch groups, especially localized skin irritation. See also Smith et al., in “Smoking cessation: a clinical study of the transdermal nicotine patch”, J Am Osteopath Assoc. 1995 November; 95(11):655-6, 661-2. See also Frederikson et al., in “High dose transdermal nicotine therapy for heavy smokers: safety, tolerability and measurement of nicotine and cotinine levels”, Psychopharmacology (Berl). 1995 December; 122(3):215-22. See also Sudan in “Nicotine skin patch treatment and adverse reactions: skin irritation, skin sensitization, and nicotine as a hapten”, J Clin Psychopharmacol. 1995 April; 15(2):145-6. See also Andersen et al. in “Chemical and pharmacologic skin irritation in man: a reflectance spectroscopic study”, Contact Dermatitis. 1991 November; 25(5):283-9. See also Gupta et al., in “Bioavailability and absorption kinetics of nicotine following application of a transdermal system”, Br J Clin Pharmacol. 1993 September; 36(3):221-7.
Skin irritation caused by nicotine transdermal patches is caused by the intrinsic skin-irritant properties of the drug itself, but also by the occlusive nature of the patch (which prevents the skin from normally “breathing”), and also by the adhesives used to maintain the skin attached to the skin. Indeed, patients are often asked to change regularly the change of application of the patch in order to prevent/minimize such unpleasant local skin reactions
Besides drawbacks commonly associated with transdermal patches, nicotine transdermal patches do also present inherent drawbacks. For instance, Klemsdal et al. (“Physical exercise increases plasma concentrations of nicotine during treatment with a nicotine patch.”, in Br J Clin Pharmacol. 1995 June; 39(6):677-9) have demonstrated that because of the occlusion, mean plasma nicotine concentration increased from 9.8 to 11.0 ng ml-1 (P=0.015) during physical exercise, and fell non-significantly from 10.5 to 10.2 ng ml-1 during rest. The increase in plasma nicotine concentration during exercise may be related to an exercise-induced increase in blood flow in the patch area. It is believed that such variations of nicotine mean plasma concentration following physical exercise is minimized and/or prevented if applying non-occlusive nicotine dosage forms.
Prather et al. in “Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men”, J Clin Pharmacol. 1993 July; 33(7):644-9, reported that nicotine Cmax and AUC values were significantly lower in obese compared with normal-sized men, and that nicotine AUC was strongly correlated to body weight and body mass index. It is believed that transdermal semi-solid dosage forms, such as transdermal gels, would minimize such variations of nicotine bioavailability since they offer a greater dosing flexibility by simply increasing or decreasing the dose of gel to be rubbed on the skin.
Woolf et al. reported that 18 children had bitten, chewed, or swallowed part of a transdermal nicotine patch. All four commercial brands of transdermal nicotine patch were represented; no brand was associated with more symptoms or an increased severity of illness. It is also highlighted that pediatric exposures to patches containing other medications, such as clonidine, have been previously reported in the past (see electronic article “Childhood Poisoning Involving Transdermal Nicotine Patches”, Pediatrics Vol. 99 No. 5 May 1997, p. e4). Indeed, patient information leaflets of transdermal patches very often emphasize the disposal guidelines of patches, which should be folded in half and thrown away out of the reach of children.
U.S. Pat. No. 4,597,961 describes an occlusive pad comprising a reservoir for liquid nicotine base to be affixed to the skin in a variety of places.
U.S. Pat. No. 5,230,896 describes a transdermal delivery system for nicotine which comprises a nicotine base, an acrylate polymer adhesive, a stabilizer and a polyester film backing.
U.S. Pat. No. 5,603,947 describes a skin or buccal patch for providing nicotine replacement therapy which comprises a matrix type laminated composite in which the matrix is composed of a mixture of nicotine in a polymer.
U.S. Pat. No. 5,633,008 describes a method of administering nicotine transdermally in which a nicotine patch, capable of administering nicotine for at least 16 hours at rates that are efficacious in smoking cessation therapy, is applied in the morning upon waking and removed prior to sleep.
U.S. Pat. No. 5,783,207 describes a nicotine-containing dosage-form comprising an attached holder member which may be used to manipulate the dosage form within the mouth of the patient.
U.S. Pat. No. 5,935,604 describes a nasal drug delivery composition comprising a complex of an ion-exchange material with nicotine or a pharmacologically-acceptable salt or derivative thereof.
U.S. Pat. No. 6,165,497 describes subsaturated rate-controlled transdermal nicotine therapeutic delivery systems which utilize an in-line adhesive to maintain the systems on the skin.
U.S. Pat. No. 6,479,076 describes compositions containing nicotine and an uncrosslinked, water-insoluble vinylpyrrolidone copolymer to be applied on the skin of patients.
U.S. Pat. No. 6,596,740 describes nicotine nasal spray compositions.
U.S. Pat. No. 6,676,959 describes nicotine-containing oral solid pharmaceutical compositions essentially comprising apolar, polar and surface-active components and giving a rapid transmucosal absorption.
U.S. Pat. No. 6,828,336 describes nicotine-containing, controlled release composition in powder form for oral administration from which nicotine release rate is not less than 70% over a 10 minute period.
U.S. Pat. No. 7,029,692 describes transdermal nicotine patches containing monoterpene ketones as odour-improving substances.
No admission is made that any reference, including any patent or patent document, cited in this specification constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in United States of America or in any other country. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinency of any of the documents cited herein.
In view of the aforementioned, there remains a need to provide a pharmaceutically acceptable transdermal or transmucosal pharmaceutical formulation or drug delivery system containing nicotine or pharmaceutically acceptable salts thereof that exhibits the advantages of both occlusive systems (high thermodynamic activity) and non-occlusive systems (low irritation and sensitization potential, and excellent skin tolerance) while overcoming the disadvantages of these systems. The novel transdermal or transmucosal pharmaceutical formulation of the present invention satisfies this need.
The formulations of the present invention as described herein below provide a number of advantages for the transdermal delivery of nicotine and its derivatives. These include, but are not limited to, continuous, steady-state delivery, which can provide sustained blood levels of the agent(s).